Substituted azepines as histamine h3 receptor antagonists, preparation and therapeutic uses

ABSTRACT

The present invention discloses novel substituted azepine compounds of Formula (I) or pharmaceutically acceptable salts thereof which have selective histamine-H3 receptor antagonist activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such azepines as well as methods of using them to treat obesity and other histamine H3 receptor-related diseases.

The present invention relates to histamine H3 receptor antagonists, andas such are useful in the treatment of disorders responsive to theinactivation of histamine H3 receptors, such as obesity, cognitivedisorders, attention deficit disorders and the like.

The histamine H3 receptor (H3R) is a presynaptic autoreceptor andhetero-receptor found in the peripheral and central nervous system andregulates the release of histamine and other neurotransmitters, such asserotonin and acetylcholine. The histamine H3 receptor is relativelyneuron specific and inhibits the release of a number of monoamines,including histamine. Selective antagonism of the histamine H3 receptorraises brain histamine levels and inhibits such activities as foodconsumption while minimizing non-specific peripheral consequences.Antagonists of the histamine H3 receptor increase synthesis and releaseof cerebral histamine and other monoamines. By this mechanism, theyinduce a prolonged wakefulness, improved cognitive function, reductionin food intake and normalization of vestibular reflexes. Accordingly,the histamine H3 receptor is an important target for new therapeutics inAlzheimer disease, mood and attention adjustments, cognitivedeficiencies, obesity, dizziness, schizophrenia, epilepsy, sleepingdisorders, narcolepsy and motion sickness.

The majority of histamine H3 receptor antagonists to date resemblehistamine in possessing an imidazole ring generally substituted in the4(5) position (Ganellin et al., Ars Pharmaceutica, 1995, 36:3, 455-468).A variety of patents and patent applications directed to antagonists andagonists having such structures include EP 197840, EP 494010, WO97/29092, WO 96138141, and W096/38142. These imidazole-containingcompounds have the disadvantage of poor blood-brain barrier penetration,interaction with cytochrome P-450 proteins, and hepatic and oculartoxicities.

Non-imidazole neuroactive compounds such as beta histamines (Arrang,Eur. J. Pharm. 1985, 111:72-84) demonstrated some histamine H3 receptoractivity but with poor potency. EP 978512 published Mar. 1, 2000discloses non-imidazole aryloxy alkylamines as histamine H3 receptorantagonists, but does not disclose the affinity, if any, of theseantagonists for recently identified histamine receptor GPRv53, describedbelow. EP 0982300A2 (pub. Mar. 1, 2000) discloses non-imidazolealkylamines as histamine HS receptor ligand which are similar to thesubject invention by having a phenoxy core structure although thesubject invention is unique in the presence of a saturated, fusedheterocyclic ring appended to the central benzene core. Furthermore thecompounds of this invention are highly selective for the H3 receptor(vs. other histamine receptors), and possess advantageous drugdisposition properties (pharmacolinetics).

Histamine mediates its activity via four receptor subtypes, H1R, H2R,H3R and a newly identified receptor designated GPRv53 [(Oda T., et al.,J. Biol. Chem. 275 (47): 36781-6 (2000)]. Alternative names for theGPRv53 receptor are PORT3 or H4R. Although relatively selective ligandshave been developed for H1R, H2R and H3R, few specific ligands have beendeveloped that can distinguish H3R from GPRv53. GPRv53 is a widelydistributed receptor found at high levels in human leukocytes.Activation or inhibition of this receptor could result in undesirableside effects when targeting antagonism of the H3R receptor. Furthermore,the identification of this new receptor has fundamentally changedhistamine biology and must be considered in the development of histamineH3 receptor antagonists.

Because of the unresolved deficiencies of the compounds described above,there is a continuing need for improved methods and compositions totreat disorders associated with histamine H3 receptors. The presentinvention provides compounds that are useful as histamine H3 receptorantagonists. In another aspect, the present invention provides compoundsthat are useful as selective antagonists of the histamine H3 receptorbut have little or no binding affinity of GPRv53. In yet another aspect,the present invention provides pharmaceutical compositions comprisingantagonists of the histamine H3 receptor. In yet another aspect, thepresent invention provides compounds, pharmaceutical compositions, andmethods useful in the treatment of obesity, cognitive disorders,attention deficit disorders and other disorders associated withhistamine H3 receptor.

The present invention is a compound structurally represented by FormulaI

or pharmaceutically acceptable salts thereof, wherein:

-   -   R¹ and R² are independently H, or —OR³N R⁴R⁵, provided only one        of R¹ and R² can be —OR³NR⁴R⁵;    -   R³ is (C₂-C₅)alkylene;    -   R⁴ is (C₁-C₄)alkyl;    -   R⁵ is (C₁-C₄)alkyl,        -   wherein R⁴ and R⁵ taken together with the nitrogen atom to            which they are attached can form a piperidinyl or            pyrrolidinyl ring;    -   X is CH₂ or CO;    -   Y and Z are —CH₂— or N, provided only one of Y and Z can be N;    -   R⁶ is hydrogen,        -   —(C₁-C₄)alkyl,        -   —CH₂-phenyl,        -   —CH₂(C₃-C₇)cycloalkyl,        -   —CO₂R⁸,        -   —SO₂R⁹,        -   —CONHR¹⁰,        -   —COR¹¹,        -   —CH₂CH₂NR¹²R¹³, or        -   —CH₂R¹⁴;    -   R⁷ is hydrogen,        -   —(C₁-C₄)alkyl,        -   —CH₂-phenyl,        -   —CH₂(C₃-C₇)cycloalkyl,        -   —CO₂R⁸,        -   —SO₂R⁹,        -   —CONHR¹⁰,        -   —COR¹¹,        -   —CH₂CH₂NR¹²R¹³, or        -   —CH₂R¹⁴;    -   Wherein;    -   R⁸ is        -   —(C₁-C₄)alkyl, or        -   —(C₃-C₇)cycloalkyl;    -   R⁹ is        -   —(C₁-C₄)alkyl,        -   —(C₃-C₇)cycloalkyl, or        -   -phenyl;    -   R¹⁰ is        -   —(C₁-C₄)alkyl, or        -   —(C₃-C₇)cycloalkyl;    -   R¹¹ is        -   —(C₁-C₄)alkyl,        -   —(C₃-C₇)cycloalkyl,        -   —CH₂NR¹²R¹³, or        -   —(C₃-C₇)cycloalkyl, wherein optionally one or more of said            carbons is replaced by N, NR¹⁰, or NCO₂R¹⁰;    -   R¹² is        -   -hydrogen, or        -   —(C₁-C₄)alkyl;    -   R¹³ is        -   -hydrogen,        -   —(C₁-C₄)alkyl,        -   —CO₂R¹⁰, or        -   -phenyl;    -   R¹⁴ is        -   —(C₁-C₄)alkyl, or        -   (C₃-C₇)cycloalkyl, wherein optionally one or more of said            carbons is replaced by N, NR¹⁰, or NCO₂R¹⁰.

While all of the compounds of the present invention are useful, certainof the compounds are particularly interesting and are preferred. Thefollowing listing sets out several groups of preferred compounds. Itwill be understood that each of the listings may be combined with otherlistings to create additional groups of preferred embodiments.

-   -   1) R¹ is —OR³NR⁴R⁵    -   2) R² is hydrogen    -   3) R³ is —CH₂CH₂CH₂—    -   4) R⁴ and R⁵ cyclize with the nitrogen to which they are        attached to form a piperidinyl ring    -   5) Y is N    -   6) Z is CH₂

Alternatively, R² is —R³NR⁴R⁵, R¹ is hydrogen, R³ is —CH₂CH₂CH₂—, R⁴ andR⁵ cyclize with the nitrogen to which they are attached to form apiperidinyl ring, Y is N and Z is CH₂. Alternatively, R² is —OR³NR⁴R⁵,R¹ is hydrogen, R³ is —CH₂CH₂CH₂—, R⁴ and R⁵ cyclize with the nitrogento which they are attached to form a piperidinyl ring, Z is N and Y isCH₂.

The present invention is a pharmaceutical composition which comprises acompound of Formula I and a pharmaceutically acceptable carrier.Pharmaceutical formulations of Formula I can provide a method ofselectively increasing histamine levels in cells by contacting the cellswith an antagonist of the histamine H3 receptor, the antagonists being acompound of Formula I.

The present invention further provides an antagonist of Formula I whichis characterized by having little or no binding affinity for thehistamine receptor GPRv53. Thus, a pharmaceutical preparation of FormulaI can be useful in the treatment or prevention of obesity, cognitivedisorders, attention deficit disorders and the like, which comprisesadministering to a subject in need of such treatment or prevention aneffective amount of a compound of Formula I. In addition, apharmaceutical preparation of Formula I can be useful in the treatmentor prevention of a disorder or disease in which inhibition of thehistamine H3 receptor has a beneficial effect or the treatment orprevention of eating disorders which comprises administering to asubject in need of such treatment or prevention an effective amount of acompound of Formula I.

General terms used in the description of compounds, compositions, andmethods herein described, bear their usual meanings. Throughout theinstant application, the following terms have the indicated meanings:

The term “GPRv53” means a recently identified novel histamine receptoras described in Oda, et al., supra. Alternative names for this receptorare PORT3 or H4R.

The term “H3R” means to the histamine H3 receptor that inhibits therelease of a number of monoamines, including histamine.

The term “H1R” means to the histamine H1 receptor subtype.

The term “H2R” means to the histamine H2 receptor subtype.

The term “selective H3R antagonists” is defined as the ability of acompound of the present invention to block forskolin-stimulated cAMPproduction in response to agonist R(−)α methylhistamine.

In the general formulae of the present document, the general chemicalterms have their usual meanings. For example:

“Alkylene” are a saturated hydrocarbyldiyl radical of straight orbranched configuration made up of from 2 to 5 carbon atoms. Includedwithin the scope of this term are ethylene, propylene, and the like.

“Alkyl” are one to four or one to eight carbon atoms such as methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric formsthereof.

“Boc” or “BOC” refer to t-butyl carbamate.

“HOBT” is 1-hydrobenzotriazole.

“Cycloalkyl” are three to seven carbon atoms such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

“Halogen” or “halo” means fluoro, chloro, bromo and iodo.

“PS-Trisamine” is Tris-(2-aminoethyl)amine polystyrene.“PS-Carbodiimide” or “PS-CDI” isN-Cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene. “PS-DIEA” isN,N-(Diisopropyl)aminomethylpolystyrene (1% inorganic antistatic agent).“PS-DMAP” is N-(methylpolystyrene)-4-(methylamino)pyridine.

“Composition” means a pharmaceutical composition and is intended toencompass a pharmaceutical product comprising the active ingredient(s),Formula I, and the inert ingredient(s) that make up the carrier.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

The term “unit dosage form” means physically discrete units suitable asunitary dosages for human subjects and other non-human animals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical carrier.

The terms “treat”, “treating”, and “treatment”, as used herein, includetheir generally accepted meanings, i.e., preventing, prohibiting,restraining, alleviating, ameliorating, slowing, stopping, or reversingthe progression or severity of a pathological condition, describedherein.

While all of the compounds of the present invention are useful, certainof the compounds are particularly interesting and are preferred. Thefollowing listing sets out several groups of preferred compounds. Itwill be understood that each of the listings may be combined with otherlistings to create additional groups of preferred embodiments.

-   -   1) R¹ is —OR³NR⁴R⁵    -   2) R² is hydrogen    -   3) R³ is —CH₂CH₂CH₂—    -   4) R⁴ and R⁵ cyclize with the nitrogen to which they are        attached to form a piperidinyl ring    -   5) Y is N    -   6) Z is CH₂

Alternatively, R² is —OR³NR⁴R⁵, R¹ is hydrogen, R³ is —CH₂CH₂CH₂—, R⁴and R⁵ cyclize with the nitrogen to which they are attached to form apiperidinyl ring, Y is N and Z is CH₂. Alternatively, R² is —R³NR⁴R⁵, R¹is hydrogen, R³ is —CH₂CH₂CH₂—, R⁴ and R⁵ cyclize with the nitrogen towhich they are attached to form a piperidinyl ring, Z is N and Y is CH₂.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutical salts,tautomers, enantiomers and other stereoisomers of the compounds, andracemic mixtures thereof. Thus, as one skilled in the art knows, certainaryls may exist in tautomeric forms. Such variations are contemplated tobe within the scope of the invention.

Some of the compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation: ${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 70:30 is achieved, theee with respect to the first enantiomer is 40%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the specific stereoisomersand enantiomers of compounds of formula I can be prepared by one ofordinary skill in the art utilizing well known techniques and processes,such as those disclosed by J. Jacques, et al., “Enantiomers, Racemates,and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel andS. H. Wilen, “Stereochemistry of Organic Compounds”, (Wiley-Interscience1994), and European Patent Application No. EP-A-838448, published Apr.29, 1998. Examples of resolutions include recrystallization techniquesor chiral chromatography.

The compounds of Formula I, when existing as a diastereomeric mixture,may be separated into diastereomeric pairs of enantiomers by, forexample, fractional crystallization from a suitable solvent, for examplemethanol or ethyl acetate or a mixture thereof. The pair of enantiomersthus obtained may be separated into individual stereoisomers byconventional means, for example by the use of an optically active acidas a resolving agent. Alternatively, any enantiomer of a compound of theformula may be obtained by stereospecific synthesis using optically purestarting materials or reagents of known configuration or throughenantioselective synthesis.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

The designation “

” refers to a bond that protrudes forward out of the plane of the page.The designation “

” refers to a bond that protrudes backward out of the plane of the page.The designation “

” refers to a bond wherein the stereochemistry is not defined.

In general, the term “pharmaceutical” when used as an adjective meanssubstantially non-toxic to living organisms. For example, the term“pharmaceutical salt” as used herein, refers to salts of the compoundsof formula I which are substantially non-toxic to living organisms. See,e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., “PharmaceuticalSalts” J. Pharm. Sci., 66:1, 1977. Typical pharmaceutical salts includethose salts prepared by reaction of the compounds of formula I with aninorganic or organic acid or base. Such salts are known as acid additionor base addition salts respectively. These pharmaceutical saltsfrequently have enhanced solubility characteristics compared to thecompound from which they are derived, and thus are often more amenableto formulation as liquids or emulsions.

The term “acid addition salt” refers to a salt of a compound of formulaI prepared by reaction of a compound of formula I with a mineral ororganic acid. For exemplification of pharmaceutical acid addition saltssee, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm.Sci., 66:1, 1977. Since compounds of this invention can be basic innature, they accordingly react with any of a number of inorganic andorganic acids to form pharmaceutical acid addition salts.

Such acid addition salts include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, phosphate, mono-hydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate,3-hexyne-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate,methoxybenzoate, phthalate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, hippurate,beta-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,mandelate and the like salts.

The pharmaceutical acid addition salts of the invention are typicallyformed by reacting the compound of formula I with an equimolar or excessamount of acid. The reactants are generally combined in a mutual solventsuch as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol,benzene, and the like. The salts normally precipitate out of solutionwithin about one hour to about ten days and can be isolated byfiltration or other conventional methods.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and acids commonly employed to formsuch salts are inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, andorganic acids, such as p-toluenesulfonic acid, methanesulfonic acid,oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid,citric acid, benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like.

The term “base addition salt” refers to a salt of a compound of formulaI prepared by reaction of a compound of formula I with a mineral ororganic base. For exemplification of pharmaceutical base addition saltssee, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm.Sci., 66:1, 1977. This invention also contemplates pharmaceutical baseaddition salts of compounds of formula I. The skilled artisan wouldappreciate that some compounds of formula I may be acidic in nature andaccordingly react with any of a number of inorganic and organic bases toform pharmaceutical base addition salts. Examples of pharmaceutical baseaddition salts are the ammonium, lithium, potassium, sodium, calcium,magnesium, methylamino, diethylamino, ethylene diamino, cyclohexylamino,and ethanolamino salts, and the like of a compound of formula I.

It should be recognized that the particular counterion forming a part ofany salt of this invention is not of a critical nature, so long as thesalt as a whole is pharmacologically acceptable and as long as thecounterion does not contribute undesired qualities to the salt as awhole.

The compounds of Formula I can be prepared by one of ordinary skill inthe art following a variety of procedures, some of which are illustratedin the procedures and schemes set forth below. The particular order ofsteps required to produce the compounds of formula I is dependent uponthe particular compound to being synthesized, the starting compound, andthe relative liability of the substituted moieties. The reagents orstarting materials are readily available to one of skill in the art, andto the extent not commercially available, are readily synthesized by oneof ordinary skill in the art following standard procedures commonlyemployed in the art, along with the various procedures and schemes setforth below, including, for example, Schemes 1 and 2.

The following Preparations and Examples are provided to better elucidatethe practice of the present invention and should not be interpreted inany way as to limit the scope of the same. Those skilled in the art willrecognize that various modifications may be made while not departingfrom the spirit and scope of the invention. All publications mentionedin the specification are indicative of the level of those skilled in theart to which this invention pertains.

The terms and abbreviations used in the instant Preparations andExamples have their normal meanings unless otherwise designated. Forexample, as used herein, the following terms have the meaningsindicated: “eq” refers to equivalents; “N” refers to normal ornormality, “M” refers to molar or molarity, “g” refers to gram or grams,“mg” refers to milligrams; “L” refers to liters; “mL” refers tomilliliters; “μL” refers to microliters; “mol” refers to moles; “mmol”refers to millimoles; “psi” refers to pounds per square inch; “min”refers to minutes; “h” or “hr” refers to hours; “° C.” refers to degreesCelsius; “TLC” refers to thin layer chromatography; “HPLC” refers tohigh performance liquid chromatography; “R_(f)” refers to retentionfactor; “R_(t)” refers to retention time; “δ” refers to part per milliondown-field from tetramethylsilane; “MS” refers to mass spectrometry,Observed Mass indicates (M+1) unless indicated otherwise. “UV” refers toultraviolet spectrometry, “¹H NMR” refers to proton nuclear magneticresonance spectrometry. In addition, “IR” refers to infraredspectrometry, and the absorption maxima listed for the IR spectra areonly those of interest and not all of the maxima observed. “RT” refersto room temperature.

Preparation 1.

7-Methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one is prepared by theprocedures similar to those described in Shtacher, G.; Erez, M.; Cohen,S. J Med Chem 1973, 16, 516.

Preparation 2.

7-methoxy-2,3,4,5,5-tetrahydro-benzo[c]azepine

7-Methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (10 g, 53 mmol) wasadded to THF (50 mL) under a nitrogen atmosphere. The stirring solutionwas chilled to 0° C. via ice bath and borane-THF complex (156 ml, 1M inTHF, 156 mmol) was added dropwise. After complete addition, the solutionwas refluxed for 2 hours and cooled to room temperature. The solutionwas quenched with 1 M HCl solution. The pH was adjusted to 9 with 1NNaOH solution and 300 mL of EtOAc was added. The solution was extractedand the organic layer was dried over magnesium sulfate and concentratedto a yellow oil. The oil was chromatographed on a biotage 75s column(10% MeOH/DCM) to yield 4.2 grams of the title compound as a white solid(45% of theory) ¹H NMR (DMSO) δ7.00 (d, 1 H), 6.63 (s, 1H), 6.59 (dd, 1H), 3.67 (s, 3 H), 3.02 (t, 2 H, 2.72 (m, 2 H), 1.55 (m, 2 H). MS (EI)178.2 m/z (M+)

Preparation 3.

2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ol hydrobromide

7-methoxy-2,3,4,5,5-tetrahydro-benzo[c]azepine (4.2 g, 22 mmol) wasdissolved in methylene chloride (50 mL) and added to boron tribromide(67 mmol, 6.4 mL) in methylene chloride (20 mL) at −78° C. under anitrogen atmosphere. The temperature was maintained below −70° C. Thereaction was stirred at −70° C. for 2 hours and the ice bath wasremoved. The reaction was stirred at room temperature for 16 hours. Theclear solution was cooled to −78° C. and methanol (15 mL) was carefullyadded. The solution was then concentrated to a brown solid. The solidwas dissolved in methanol (50 mL) and methylene chloride (40 mL) wasadded. The solution was concentrated to half-volume and hexanes wereadded (40 mL). The solution was concentrated to half volume and ethylacetate (20 mL) was added. The solution was concentrated to a volume to20 mL and the solution was filtered to obtain a white granular solid(4.2 g, 45% of theory) ¹H NMR (DMSO) δ 9.52 (s, 1H), 8.70 (br, 2H), 7.19(d, 1H), 6.58 (m, 2H), 4.23 (s, 2H), 3.33 (m, 2H), 2.88 (m, 2H), 1.70(m, 2H). MS (ES) 164.1 m/z (M-HBr). Elemental analysis; Calculatedvalues: C, 49.19; H, 5.78; N, 5.55; Observed values: C, 49.48; H, 5.78;N, 5.55.

Preparation 4.

7-Hydroxy-1,3,4,5-tetrahydro-benzo[c]azepine-2-carboxylic acidtert-butyl ester

2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ol hydrobromide (6.50 g, 26 mmol)was slurried in methylene chloride (100 mL). Triethylamine (79 mmol) wasadded and the slurry was cooled to 5° C. via ice bath. BOC anhydride wasdissolved in methylene chloride (20 mL) and added dropwise to thesolution. The ice bath was removed and the solution was allowed to stirat room temperature for four hours. The solution was concentrated to abrown solid and 40 ml of a 1:1 methylene chloride/EtOAc solution wasadded and the solution was filtered. The filtrate was concentrated to abrown oil that was chromatographed (20% EtOAc/Hex) to give a white solid(6.3 g, 90% of theory). ¹H NMR (DMSO) δ9.15 (s, 1H), 6.97 (d, 1H), 6.60(s, 1H), 6.49 (d, 1H), 4.23 (s, 2H), 3.52 (br m, 2H), 2.72 (br m, 2H),1.59 (br m, 2H), 1.33 (s, 9). ¹³C NMR (DMSO) δ 156.24, 142.99, 129.41,116.41, 111.57, 78.29, 50.95, 49.57, 34.58, 28.02. Elemental analysis;Calculated values: C, 68.42; H, 8.04; N, 5.32; Observed values: C,68.54; H, 8.15; 5.24.

Preparation 5.

7-Hydroxy-1,2,4,5-tetrahydro-benzoldlazepine-3-carboxylic acidtert-butyl ester; prepared by the method reported in Austin et al.,Bioorganic Med Chem Letts, 2000, 10, 2553.

Preparation 6.

7-(3-Piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester; prepared in quantitative yield from7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (2 g, 7.6 mmol) and 1-(3-chloropropyl)-piperidine (1.5mL, 9.3 mmol) by the method of Procedure A. (See herein example 1) Aportion was purified by flash chromatography on silica gel (30:1 DCM/7NNH₃ in methanol). MS (ESI), M+H: 389 (100%).

Procedure A: To a stirred solution of7-hydroxy-1,3,4,5-tetrahydro-benzo[c]azepine-2-carboxylic acidtert-butyl ester (2 g, 7.6 mmol) in dry dimethylformamide (DMF) (16 mL)at room temperature under N₂, is added sodium hydride (60% dispersion,0.36 g, 9.12 mmol) portion wise. The mixture is stirred for 15 minutes,and 1-(3-chloropropyl)-piperidine (1.5 mL, 9.3 mmol) is added, followedby sodium iodide (1.09 g, 7.23 mmol). After heating for 4 hours at 70°C., the reaction mixture is cooled to room temperature, poured intowater, extracted three times with ethyl acetate, dried over anhydrouspotassium carbonate and concentrated in vacuo, to providequantitatively,7-(3-Piperidin-1-yl-propoxy)-1,3,4,5-tetrahydro-benzo[c]azepine-2-carboxylicacid tert-butyl ester. A portion was purified by flash chromatography onsilica gel (30:1 DCM/7N NH₃ in methanol). MS (ESI), M+H: 389 (100%).

7-(3-Piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepinedihydrochloride; prepared (2.6 g, 100%) from7-(3-piperidin-1-yl-propoxy)-1,3,4,5-tetrahydro-benzo[c]azepine-2-carboxylicacid tert-butyl ester (2.8 g, 7.22 mmol) by the method of Procedure H.(See herein Example 22). MS (APCI), M+H: 289 (100%).

7-(3-Piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[c]azepine-2-carboxylicacid isopropylamide prepared as a pale oil (64 mg, 99%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (50mg, 0.173 mmol) and isopropyl isocyanate (24 mg, 0.208 mmol) by themethod of Procedure D (See herein Example 16), except SCX chromatographywas not conducted. ¹H NMR (CDCl₃) δ 7.08 (d, 1H), 6.73 (d, 1H), 6.65(dd, 1H), 4.32 (s, 2H), 4.15 (d, 1H), 3.98 (t, 2H), 3.85 (m, 1H), 3.67(m, 2H), 2.89 (m, 2H), 2.46 (t, 2H), 2.40 (m, 4H), 1.96 (m, 2H), 1.78(m, 2H), 1.59 (qt, 4H), 1.44 (m, 2H), 1.07 (d, 6H); MS (APCI): M+H:374(100%).

Procedure B: To a stirred solution of7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (75mg, 0.260 mmol) in 10:1 dichloroethane(DCE)/methanol (3.6 mL) containingacetic acid (0.1 equivalent) at room temperature under N₂, is addedbenzaldehyde (41 mg, 0.386 mmol). After 15 minutes, sodiumtriacetoxyborohydride (114 mg, 0.54 mmol) is added. Stirring iscontinued for 30 minutes (or until starting material was consumed byTLC) and the mixture was loaded directly onto a Varian SCX column (10g). The column was washed with DCM and methanol, and the desiredcompound was then eluted with a 7N NH₃ in methanol, to provide2-Benzyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a pale oil (54 mg 55%). ¹H NMR (CDCl₃) δ 7.26 (m, 5H), 6.83(d, 1H), 6.71 (s, 1H), 6.60 (dd, 1H), 3.99 (m, 2H), 3.81 (s, 2H), 3.50(s, 2H), 3.08 (m, 2H), 2.84 (m, 2H), 2.54 (m, 2H), 2.47 (bs, 4H), 2.02(m, 2H), 1.74 (bs, 2H), 1.64 (m, 4H), 1.48 (m, 2H); MS (APCI): M+H: 379(100%).

2-Cyclohexylmethyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;prepared as a pale oil (56 mg, 86%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (50mg, 0.174 mmol) and cyclohexanecarboxaldehyde (30 mg, 0.260 mmol) by themethod of Procedure B. (See herein Example 4). ¹H NMR CDCl₃) δ 6.99 (d,1H), 6.69 (d, 1H), 6.62 (dd, 1H), 3.99 (t, 2H), 3.87 (s, 2H), 3.11 (m,2H), 2.84 (m, 2H), 2.59 (t, 2H), 2.53 (bs, 4H), 2.14 (d, 2H), 2.04 (m,2H), 1.70 (m, 11H), 1.41-1.51 (m, 3H), 1.20-1.28 (m, 3H), 0.83 (m, 2H);MS (APCI): M+H: 385 (100%).

2-Isopropyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;prepared as a pale oil (67 mg, 78%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (75mg, 0.26 mmol) by the method of Procedure G (see herein Example 21),except that the dihydrochloride was not prepared. ¹H NMR (CDCl₃) δ 7.03(d, 1H), 6.69 (d, 1H), 6.63 (dd, 1H), 3.97 (t, 2H), 3.77 (s, 2H), 3.08(t, 2H), 2.82 (m, 2H), 2.78 (sept, 1H), 2.48 (t, 2H), 2.42 (bs, 4H),1.98 (t, 1H), 1.95 (t, 1H), 1.75 (m, 2H), 1.60 (m, 4H), 1.45 (m, 2H),1.09 (d, 3H), 1.08 (d, 3H); MS (APCI): M+H: 331 (46%).

3-Cyclohexylmethyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepinedimaleate; prepared by the method of Procedure B. (See herein Example4). The free base was converted to its dimaleate (2 equivalents maleicacid in boiling ethyl acetate) and recrystallized from ethanol/ethylacetate. Drying under high vacuum at 100° C gave the title compound as awhite solid (4.0 g). ¹H NMR (free base in CDCl₃) δ 6.97 (d, 1H), 6.65(d, 1H), 6.62 (dd, 1H), 3.97 (t, 2H), 2.84 (m, 4H), 2.57 (m, 4H), 2.46(t, 2H), 2.40 (bs, 4H), 2.22 (d, 2H), 1.95 (m, 2H), 1.80 (bd, 2H), 1.70(bm, 3H), 1.59 (m, 4H), 1.50 (m, 1H), 1.44 (m, 2H), 1.14-1.28 (m, 3H),0.88 (m, 2H); MS (APCI), M+H: 385 (100%).

2-Dimethylamino-1-[7-(3-piperidin-1-yl-propoxy)-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-ethanone;prepared as a pale oil (12 mg, 18%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (50mg, 0.173 mmol) and N,N-dimethylglycine (22 mg, 0.208 mmol) by themethod of Procedure J (see herein Example 28). ¹H NMR (CDCl₃) δ 7.26 (d,0.5H), 7.03 (d, 0.5H), 6.73 (d, 0.5H), 6.69 (d, 0.5H), 6.65 (m, 1H),4.65 (s, 1H), 4.49 (bs, 1H), 3.97 (q, 2H), 3.79 (bm, 2H), 3.11 (s, 1H),3.03 (s, 1H), 2.90 (m, 2H), 2.46 (m, 2H), 2.39 (bs, 4H), 2.31 (s, 3H),2.21 (s, 3H), 1.95 (m, 2H), 1.81 (m, 2H), 1.59 (m, 4H). 1.44 (m, 2H); MS(APCI), M+H: 374 (100%).

2-Ethyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;prepared as a pale oil (31 mg, 94%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (30mg, 0.104 mmol) and acetaldehyde (excess) by the method of Procedure B,(See herein Example 4) except that flash chromatography was notperformed. H NMR (CDCl₃) δ 7.02 (d, 1H), 6.69 (d, 1H), 6.62 (dd, 1H),3.97 (t, 2H), 3.84 (s, 2H), 3.09 (m, 2H), 2.83 (m,2H), 2.39-2.49 (m,8H), 1.96 (m, 2H), 1.72 (m, 2H), 1.59 (m, 4H), 1.44 (m, 2H),1.07 (t,3H); MS (APCI), M+H: 317 (100%).

3-Benzyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;prepared as a pale oil (56 mg, 86%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (50mg, 0.174 mmol) and benzaldehyde (28 mg, 0.264 mmol) by the method ofProcedure B. (See herein Example 4). ¹H NMR (CDCl₃) δ 7.30-7.36 (m,4H1), 7.22-7.27 (m, 1H), 6.96 (d, 1H), 6.63 (d, 1H), 6.61 (dd, 1H), 3.96(t, 2H), 3.63 (s, 2H), 2.85 (m, 4H), 2.61 (m, 4H), 2.52 (t, 2H), 2.46(bs, 4H), 1.99 (m, 2H), 1.63 (m, 4H), 1.45 (m, 2H); MS (APCI): M+H: 379(100%).

3-Cyclohexylmethyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;prepared as a pale oil (44 mg, 66%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (50mg, 0.174 mmol) and cyclohexanecarboxaldehyde (29 mg, 0.259 mmol) by themethod of Procedure B. (See herein Example 4). ¹H N (CDCl₃) δ 6.97 (d,1H), 6.65 (d, 1H), 6.61 (dd, 1H), 3.97 (t, 2H), 2.84 (m, 4H), 2.52-2.62(m, 6H), 2.48 (bs, 4H), 2.24 (d, 2H), 2.01 (m, 2H), 1.80 (bd, 2H),1.62-1.74 (m, 7H), 1.44-1.56 (m, 3H), 1.12-1.30 (m, 3H), 0.88 (m, 2H);MS (APCI), M+H: 385 (100%).

3-Methanesulfonyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;prepared as a pale solid (49 mg, 77%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (50mg, 0.173 mmol) and methanesulfonyl chloride (24 mg, 0.208 mmol) by themethod of Procedure D (see herein Example 16), except flashchromatography was not conducted. ¹H NMR (CDCl₃) δ 7.03 (d, 1H), 6.69(d, 1H), 6.68 (dd, 1H), 3.99 (t, 2H), 3.42 (m, 4H), 2.97 (m, 4H), 2.77(s, 3H), 2.55 (t, 2H), 2.49 (bs, 4H), 2.02 (m, 2H), 1.65 (m, 4H), 1.47(m, 2H); MS (APCI), M+H: 367 (100%).

7-(3-Piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid isopropylamide; Procedure C: To a stirred mixture7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (50mg, 0.173 mmol) at room temperature in dry DCM (4 mL) under dry N₂ wasadded isopropyl isocyanate (18 mg, 0.208 mmol) and stirring wascontinued overnight. PS-Trisamine (Argonaut, 4.46 mmol/g, 200 mg, 0.892mmol) was added and stirring was continued for several hours. Themixture was suction filtered, the scavenger was rinsed with DCM, and thecombined filtrates were concentrated in vacuo. The crude material wasloaded onto a Varian SCX column (10 g), the column was washed with DCMand methanol, and the desired compound was then eluted with 7N NH₃ inmethanol to provide the title compound as a pale oil (58 mg, 90%). ¹HNMR (CDCl₃) δ 6.99 (d, 1H), 6.67 (d, 1H), 6.64 (dd, 1H), 4.26 (d, 1H),4.02 (m, 1H), 3.98 (t, 2H), 3.53 (m, 2H), 3.49 (m, 2H), 2.87 (m, 4H),2.55 (t, 2H), 2.48 (bs, 4), 2.02 (m, 2H), 1.65 (m, 4H), 1.47 (m, 2H),1.18 (d, 6H); MS (APCI), M+H: 374 (100%).

3-Ethyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;prepared as a pale oil (23 mg, 70%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (30mg, 0.104 mmol) and acetaldehyde (excess) by the method of Procedure B,(See herein Example 4) except that flash chromatography was notperformed. ¹H NMR (CDCl₃) δ 6.98 (d, 1H), 6.66 (d, 1H), 6.63 (dd, 1H),3.98 (t, 2H), 2.89 (m, 4H), 2.66 (m, 4H), 2.60 (q, 2H), 2.51 (t, 2H),2.45 (bs, 4H), 1.99 (m, 2H), 1.62 (m, 4H), 1.46 (m, 2H), 1.11 (t, 3H);MS (APCI), M+H: 317 (100%).

Cyclopentyl-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-methanone;prepared as a pale oil (65 mg, 81%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (60mg, 0.208 mmol) and cyclopentanecarboxylic acid (30 mg, 0.26 mmol) bythe method of Procedure J (see herein Example 28). ¹H NMR (CDCl₃) δ 7.02(m,1H), 6.67 (m, 2H), 3.98 (t, 2H), 3.71 (m, 2H), 3.63 (m, 2H), 2.97(qt, 1H), 2.86 (m, 4H), 2.53 (t, 2H), 2.47 (bs, 4H), 2.00 (m, 2H), 1.85(m, 4H), 1.76 (m, 2H), 1.62 (m, 6H), 1.46 (m, 2H); MS (APCI), M+H: 385(100%).

3-Benzenesulfonyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;Procedure D: To a stirred mixture7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (30mg, 0.104 mmol) PS-DMAP (Argonaut, 1.48 mmol/g, 14 mg, 0.021 mmol), andPS-DIEA (Argonaut, 3.83 mmol/g, 81 mg, 0.312 mmol), at room temperaturein dry DCM (4 mL) under N₂ was added benzenesulfonyl chloride (47 mg,0.268 mmol) and stirring was continued overnight. PS-Trisamine(Argonaut, 4.46 mmol/g, 200 mg, 0.892 mmol) was added and stirring wascontinued for several hours. The mixture was suction filtered, thescavenger was rinsed with DCM, and the combined filtrates wereconcentrated in vacuo. The crude material was loaded onto a Varian SCXcolumn (10 g), the column was washed with DCM and methanol, and thedesired compound was then eluted with 7N NH₃ in methanol. Furtherpurification by flash chromatography on silica gel (20:1 DCM/7N NH₃ inmethanol) furnished the title compound (38 mg, 85%). ¹H NMR (CDCl₃) δ7.75 (m, 2H), 7.45-7.53 (m, 3H), 6.96 (d, 1H), 6.61 (m, 2H), 3.94 (t,

2H), 3.29 (m, 4H), 2.94 (m, 4H), 2.51 (t, 2H), 2.45 (bs, 4H), 1.98 (m,2H), 1.63 (m, 4H), 1.46 (m, 2H); MS (APCI), M+H: 429 (100%).

2-Isopropyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepinedihydrochloride; prepared by the method of Procedure G. (See hereinExample 21). The free base was converted to its dihydrochloride (excess2M HCl in ether/DCM) to provide the title compound as a white solid (5.5g). ¹H NMR (free base in CDCl₃) δ 7.03 (d, 1H), 6.69 (d, 1H), 6.62 (dd,1H), 3.97 (t, 2H), 3.74 (s, 2H), 3.06 (t, 2H), 2.83 (m, 2H), 2.77 (sept,1H), 2.46 (t, 2H), 2.40 (bs, 4H), 1.96 (m, 2H), 1.74 (m, 2H), 1.59 (m,4H), 1.45 (m, 2H), 1.08 (d, 3H), 1.06 (d, 3H); MS (APCI): M+H: 331(40%).

3-Isopropyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;prepared as a pale oil (56 mg, 97%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (50mg, 0.174 mmol) by the method of Procedure G, (See herein Example 21),except that the dihydrochloride was not prepared. ¹H NMR (CDCl₃) δ 6.98(d, 1H), 6.67 (d, 1H), 6.63 (dd, 1H), 3.96 (t, 2H), 2.97 (sept, 1H),2.86 (m, 4H), 2.64 (m, 4H), 2.47 (m, 2H), 2.40 (bs, 4H), 1.96 (m, 2H),1.59 (m, 4H), 1.43 (m, 2H), 1.03 (d, 6H); MS (APCI), M+H: 331 (100%).

1-[7-(3-Piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethanone;Procedure E: To a stirred mixture of7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (35mg, 0.121 mmol), PS-DMAP (Argonaut, 1.48 mmol/g, 16 mg, 0.02 mmol),PS-DIEA (Argonaut, 3.83 mmol/g, 138 mg, 0.53 mmol) and triethylamine(2.3 μL, 0.016 mmol) in dry DCM (3.5 mL) at room temperature under dryN₂ was added acetic anhydride (16 mg, 0.158 mmol). After 2 hours,triamine-3 (Silicycle, 1.42 mmol/g, 345 mg, 0.490 mmol) and isocyanate-3(Silicycle, 1.21 mmol/g, 400 mg, 0.48 mmol) are added and stirring wascontinued for several hours. The mixture was suction filtered, thescavengers were rinsed with DCM, and the filtrate was concentrated invacuo. Purification of the residue by flash chromatography on silica(20:1 DCM/7N NH₃ in methanol), gave the title compound as a pale oil (25mg, 63%). ¹H NMR (CDCl₃) δ 7.00 (m, 1H), 6.60-6.66 (m, 2H), 3.99 (t,2H), 3.67 (m, 2H), 3.53 (m, 2H), 2.75-2.87 (m, 10H), 2.19 (m, 2H), 2.16(s, 1.5H), 2.15 (s, 1.5H), 1.83 (m, 4H), 1.54 (bs, 2H); MS (APCI), M+H:331 (100%).

3-Cyclopentylmethyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;Procedure F: A stirred solution ofcyclopentyl-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-methanone(40 mg, 0.104 mmol) and lithium aluminum hydride (1M in THF, 0.21 mL,0.21 mmol) in dry THF (5 mL) under dyr N₂ was refluxed for 3 hours,cooled to 0° C., and quenched cautiously with excess sodium sulfatedecahydrate. After stirring for 1-2 additional hours, the mixture wasfiltered with suction, the precipitated salts were washed withadditional THF, and the combined filtrates concentrated in vacuo. Theresidue was loaded directly onto a Varian SCX column (10 g). The columnwas washed with DCM and methanol, and the desired compound was theneluted with 7N NH₃ in methanol. Further purification by flashchromatography on silica gel or preparative TLC (20:1 DCM/7N NH₃ inmethanol) afforded the title compound as a pale oil (31 mg, 81%). ¹H NMR(CDCl₃) δ 6.96 (d, 1H), 6.63 (d, 1H), 6.60 (dd, 1H), 3.96 (t, 2H), 2.86(m, 4H), 2.66 (m, 4H), 2.57 (t, 2H), 2.51 (bs, 4H), 2.44 (d, 2H), 2.09(sept, 1H), 2.03 (m, 2H), 1.75 (m, 2H), 1.66 (m, 4H), 1.44-1.61 (m, 6H),1.19 (m, 2H); MS (APCI), M+H: 371 (100%).

2-Isopropyl-7-(2-piperidin-1-yl-ethoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine,dihydrochloride; Procedure G: A stirred solution of7-(2-piperidin-1-yl-ethoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepinedihydrochloride (70 mg, 0.202 mmol), acetone (1 mL), and sodiumcyanoborohydride (40 mg, 0.636 mmol) in 1:1 DCE/methanol containingacetic acid (3 drops) was heated to 50° C. in a sealed tube overnight.After cooling to room temperature, the mixture was loaded directly ontoa Varian SCX column (10 g). The column was washed with DCM and methanol,and the desired compound was then eluted with 7N NH₃ in methanol. Thismaterial was converted to its dihydrochloride (2M HCl in ether/DCM),which was isolated as pale yellow solid (46 mg, 59%): ¹H NMR (free basein CDCl₃) δ 7.05 (d, 1H), 6.71 (d, 1H), 6.64 (d, 1H), 4.09 (t, 2H), 3.81(s, 2H), 3.11 (m, 2H, 2.83 (m, 2H), 2.81 (m, 1H), 2.76 (m, 2H), 2.51(bs, 4H), 1.77 (bm, 2H), 1.61 (m, 4H), 1.45 (bm, 2H), 1.11 (d, 6H); MS(APCI), M+H: 317 (100%).

7-(2-Piperidin-1-yl-ethoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepinedihydrochloride; Procedure H: To a stirred solution of7-(2-piperidin-1-yl-ethoxy)-1,3,4,5-tetrahydro-benzo[c]azepine-2-carboxylicacid tert-butyl ester (113 mg, 0.302 mmol) in DCM (2 mL) was added 4MHCl in dioxane (1 mL, 4.0 mmol) at room temperature. After 2 hours oruntil starting material was consumed by TLC, the mixture wasconcentrated in vacuo. The crude material was twice dissolved in drymethanol and concentrated in vacuo, and the solid was triturated withether, filtered, and dried. The title compound was obtained as a paleyellow solid (90 mg, 86%). ¹H NMR (free base in CDCl₃) δ 7.04 (bd, 1H),6.74 (d, 1H), 6.63 (d, 1H), 4.10 (t, 2H), 3.90 (bs, 2H), 3.19 (bs, 2H),2.89 (bm, 2H), 2.78 (bm, 2H), 2.53 (bs, 4H), 1.75 (bs, 2H), 1.63 (bm,4H), 1.46 (bm, 2H); MS (APCI), M+H: 275 (100%).

2-Methanesulfonyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;prepared as a pale oil (72 mg, 96%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (60mg, 0.208 mmol) and methanesulfonyl chloride (24 mg, 0.208 mmol) by themethod of Procedure D (see herein Example 16), except SCX chromatographywas not conducted. ¹H NMR (CDCl₃) δ 7.08(d, 1H), 6.73 (d, 1H), 6.65 (dd,1H), 4.46 (s, 2H), 4.03 (t, 2H), 3.74 (m, 2H), 2.95 (m, 2H), 2.86 (m,6H), 2.48 (s, 3H), 2.25 (m, 2H), 1.84-1.91 (m, 6H), 1.58 (bs, 2H); MS(APCI): M+H: 367 (100%)

7-(3-Piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;prepared as the dihydrochloride (2.6 g, 87%) from7-(3-piperidin-1-yl-propoxy)-1,3,4,5-tetrahydro-benzo[d]azepine-2-carboxylicacid tert-butyl ester (3.2 g, 8.25 mmol) by the method of Procedure H(see herein Example 22). A portion was free based (aqueous saturatedsodium bicarbonate/DCM) to provide the title compound as a pale oil. ¹HNMR (CDCl₃) δ 7.00 (d, 1H), 6.68 (d, 1H), 6.65 (dd, 1H), 4.91 (bs, 1H)3.98 (t, 2H), 3.04 (m, 4H), 2.95 (m, 4H), 2.51 (t, 2H), 2.44 (bs, 4H),1.99 (m, 2H), 1.62 (m, 4H), 1.45 (m, 2H); MS (APCI), M+H: 289 (100%).

(S)-(1-Methyl-pyrrolidin-2-yl)-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-methanone;prepared as a pale oil (40 mg, 48%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (60mg, 0.208 mmol) and N-methyl-L-proline (54 mg, 0.416 mmol) by the methodof Procedure J (see herein Example 28). ¹H NMR (CDCl₃) δ 6.96-7.02 (m,1H), 6.61-6.69 (m, 2H), 3.95 (t, 2H), 3.60-3.78 (m, 4H), 3.15 (m, 1H),3.09 (t, 1H), 2.83 (m, 4H), 2.44 (t, 2H), 2.37 (bs, 4H), 2.30 (s, 3H),2.22 (m, 1H), 2.05-2.14 (m, 1H), 1.73-1.99 (m, 5H); 1.57 (m, 4H), 1.41(m, 2H); MS (APCI), M+H: 400 (100%).

2-Phenylamino-1-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethanone;prepared as a pale oil (50 mg, 57%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (60mg, 0.208 mmol) and N-phenylglycine (39 mg, 0.26 mmol) by the method ofProcedure J (see herein Example 28). ¹H NMR (CDCl₃) δ 9.07 (bs, 0.25 H),7.54 (d, 0.75H), 7.30 (t, 0.75H), 7.07-7.15 (m, 1.5H), 6.97 (m, 1H),6.56-6.67 (m, 4H), 4.89 (m, 0.75H), 4.06 (m, 0.75H), 3.88-3.94 (m, 3H),3.71 (m, 2H), 3.49 (m, 1.5H), 2.97 (m, 0.75H), 2.79-2.89 (m, 3.25H),2.52 (t, 2H), 2.46 (bs, 4H), 1.98 (m, 2H), 1.61 (m, 4H), 1.41 (m, 2H);MS (APCI), M+H: 422 (100%).

2-Dimethylamino-1-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethanone;prepared as a pale oil (47 mg, 60%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (60mg, 0.208 mmol) and N,N-dimethylglycine (54 mg, 0.52 mmol) by the methodof Procedure J (see herein Example 28). ¹H NMR (CDCl₃) δ 6.99 (m, 1H),6.61-6.68 (m, 2H), 3.95 (t, 2H), 3.62-3.70 (m, 4H), 3.16 (s, 2H), 2.84(m, 4H), 2.45 (t, 2H), 2.38 (bs, 4H), 2.27 (s, 6H), 1.94 (m, 2H), 1.57(m, 4H), 1.41 (m, 2H); MS (APCI), M+H: 374 (100%).

(S)-2-[7-(3-Piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[a]azepine-3-carbonyl]-pyrrolidine-1-carboxylicacid tert-butyl ester; Procedure J: A mixture of7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70mg, 0.242 mmol), N-(tert-butoxycarbonyl)-L-proline (104 mg, 0.485 mmol),PS-Carbodiimide (Argonaut, 1.32 mmol/g, 367 mg, 0.485 mmol) and1-hydroxybenzotriazole (HOBt) (49 mg, 0.363 mmol) in dry 1:1 DCM/DMF (10mL) under dry N₂ was stirred at room temperature overnight. PS-Trisamine(Argonaut, 4.46 mmol/g, 480 mg, 2.14 mmol) was added and stirring wascontinued for several hours. The mixture was suction filtered, thescavenger was rinsed with DCM, and the combined filtrates wereconcentrated in vacuo. The crude material was loaded onto a Varian SCXcolumn (10 g), the column was washed with DCM and methanol, and thedesired compound was eluted with 7N NH₃ in methanol. Furtherpurification by flash chromatography on silica gel (20:1 DCM/7N NH₃ inmethanol) provided the title compound as a pale oil (77 mg, 66%). ¹H NMR(CDCl₃) δ 6.91-6.98 (m, 1H), 6.56-6.63 (m, 2H), 4.70 (m, 0.5H), 4.55(dd, 0.5), 3.91 (m, 2H), 3.15-3.75 (m, 6H), 2.70-3.12 (m, 4H), 2.53 (m,2H), 2.47 (bs, 4H), 1.86-2.18 (m, 4H), 1.78 (m, 2H), 1.62 (m, 4H),1.32-1.41 (m, 11H); MS (APCI), M+H−100: 386 (100%).

Methyl-{2-oxo-2-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethyl)}-carbamicacid tert-butyl ester, prepared as a pale oil (60 mg, 54%) from7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70mg, 0.242 mmol) and N-(tert-butoxycarbonyl)-sarcosine (104 mg, 0.485mmol) by the method of Procedure J (see herein Example 28). ¹H NMR(CDCl₃) δ 7.01 (m, 1H), 6.67 (m, 2H), 4.14 (s, 1.3H), 4.06 (s, 0.7H),3.98 (t, 2H), 3.69 (m, 2H), 3.52 (m, 2H), 2.93 (s, 3H), 2.86 (m, 4H),2.56-2.62 (t, 2H), 2.49-2.56 (bs, 4H), 2.02-2.06 (m, 2H), 1.65-1.70 (m,4H), 1.45-1.49 (m, 5.9H), 1.44 (s, 3.1H), 1.48 (m, 2H); MS (APCI), M+H:460 (100%).

2-Methylamino-1-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethanonedihydrochloride; prepared as a pale oil (35 mg, 68%) frommethyl-{2-oxo-2-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethyl}-carbamicacid tert-butyl ester (55 mg, 0.12 mmol) by the method of Procedure H(see herein Example 22). ¹H NMR (CD₃OD) δ 7.08 (m, 1H), 6.76 (m, 2H),4.15 (bm, 2H), 4.08 (bm, 2H), 3.69 (m, 2H), 3.57 (m, 4H), 3.31 (m, 2H),2.98 (bm, 4H), 2.88 (bm, 2H), 2.75 (s, 3H), 2.25 (bs, 2H), 1.95 (bm,2H), 1.85 (bm, 3H), 1.56 (bm, 1H); MS (APCI), M+H: 360 (100%).

Dimethyl-{2-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethyl}-amine;prepared as a pale oil (26 mg, 87%) from2-dimethylamino-1-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethanone(31 mg, 0.083 mmol) by the method of Procedure F (see herein Example20). Flash chromatography was performed twice. ¹H NMR (CDCl₃) δ 6.97 (d,1H), 6.63 (m, 2H), 3.96 (t, 2H), 2.85 (m, 4H), 2.64 (m, 6H), 2.45 (m,4H), 2.39 (bs, 4H), 2.25 (s, 6H), 1.95 (m, 2H), 1.58 (m, 4H), 1.43 (m,2H); MS (APCI), M+H: 360 (100%).

(S)-3-(1-Methyl-pyrrolidin-2-ylmethyl)-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;prepared as a pale oil (11 mg, 45%) from(S)-(1-methyl-pyrrolidin-2-yl)-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-methanone(25 mg, 0.063 mmol) by the method of Procedure F (see herein Example20). Flash chromatography was performed twice. ¹H NMR (CDCl₃) δ 6.96 (d,1H), 6.65 (bs, 1H), 6.63 (dd, 1H), 3.97 (t, 2H), 3.06 (t, 1H), 2.84 (m,4H), 2.61-2.71 (m, 5H), 2.31-2.48 (m, 8H), 2.43 (s, 3H), 2.18 (m, 1H),1.92-2.05 (m, 3H), 1.68-1.84 (m, 2H), 1.56 (m, 5H), 1.43 (m, 2H); MS(APCI), M+H: 386 (100%).

[7-(3-Piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-pyrrolidin-2-yl-methanonedihydrochloride; prepared as a pale oil (50 mg, 80%) from2-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carbonyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (67 mg, 0.138 mmol) by the method of Procedure H(see herein Example 22). ¹H NMR (CDCl₃) δ 12.01 (s, 1H), 11.64 (s, 1H),7.82 (bd, 1H), 7.02 (d, 1H), 6.68 (bd, 1H), 6.65 (bs, 1H), 4.83 (bs,1H), 4.07 (bs, 2H), 3.89 (m, 1H), 3.60 (bs, 4H), 3.50 (bm, 2H), 3.19(bs, 2H), 3.00 (bm, 1H), 2.85 (bm, 3H), 2.70 (bm, 2H), 2.54 (bm, 1H),2.43 (bs, 2H), 2.31 (bm, 2H), 2.19 (bm, 1H), 2.06 (bm, 1H), 1.89 (bm,5H), 1.43 (bm, 1H); MS (APCI), M+H: 386(100%).

Phenyl-(2-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethyl}-amine;prepared as a pale oil (9 mg, 51%) from2-phenylamino-1-[7-(3-piperidin-1-yl-propoxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-ethanone(18 mg, 0.043 mmol) by the method of Procedure F (see herein Example20). Flash chromatography was performed twice. ¹H NMR (CDCl₃) δ 7.20 (t,2H), 6.98 (d, 1H), 6.62-6.73 (m, 5H), 4.42 (bs, 1H), 3.97 (t, 2H), 3.17(t, 2H), 2.85 (bm, 4H), 2.74 (t, 2H), 2.65 (bt, 4H), 2.49 (bt, 2H), 2.41(bs, 4H), 1.96 (m, 2H), 1.60 (m, 4H), 1.44 (m, 2H); MS (APCI), M+H: 408(100%).

Preparation 7.

7-Methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one is prepared by theprocedures similar to those described in Shtacher, G.; Erez, M.; Cohen,S. J Med Chem 1973, 16, 516.

Preparation 8.

7-Hydroxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one is prepared by theprocedures similar to those described in Fisher, M. J. et al; J Med Chem1999, 42, 4875.

Preparation 9.

2-Ethyl-7-hydroxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one

To a mixture of 7-methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (0.50g, 2.6 mmol) in THF (15 mL) is added sodium hydride (60% mineral oilsuspension, 150 mg). The suspension is heated at reflux for 1 h, andcooled to room temperature. Ethyl iodide (2.1 mL, 26 mmol) is added, andthe mixture is stirred at room temperature overnight. The mixture ispartitioned between EtOAc and water. After the aqueous phase isextracted with EtOAc (2×), the combined organic phase is washed withbrine and dried (MgSO₄). After removal of the solvent, the residue ispurified by flash chromatography (Biotage 40M SiO₂, elute 40%EtOAc:hexane—80% EtOAc:hexane, linear gradient) to yield2-Ethyl-7-methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one as a colorlessoil (0.39 g, 68%). The material is dissolved in CH₂Cl₂ (10 mL) andcooled to −78° C. To the cooled mixture is added a solution of borontribromide (1 M, 6.2 mL, 6.2 mmol) in CH₂Cl₂. After 0.5 h, thetemperature is warmed to 0° C. and stirred for 2 h. After the reactionis carefully quenched with ice, EtOAc and water is added, and themixture is vigorously stirred overnight. The phases are separated, andthe organic phase is extracted with EtOAc (2×). The combined organicphase is washed with brine and dried (MgSO₄). The solvent is removed invacuo, and the residue is purified by flash chromatography (Biotage 40MSiO₂, elute 40% EtOAc:hexane—80% EtOAc:hexane, linear gradient) toprovide 2-Ethyl-7-hydroxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (0.135g, 37%). MS (ES+)

7-(3-Piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-benzo[c]azepin-1-one

Procedure K: A mixture of7-hydroxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (0.38 g, 2.15 mmol,Cs₂CO₃ (1.40 g, 4.3 mmol), KI (35.6 mg, 0.21 mmol), andN-(3-chloropropyl)piperidine (0.42 g, 2.6 mmol) in dioxane (25 mL) isheated at 90° C. for 20 h. The mixture is partitioned between EtOAc andwater. The phases are separated, and the aqueous phase is extracted withEtOAc (2×). The combined organic phase is washed with brine, dried(MgSO₄), and concentrated in vacuo. The resulting solid is trituratedwith petroleum ether and filtered to give the title compound as a whitesolid (0.34 g, 52%). MS(ES+) 303.4(M+H)⁺.

2-Ethyl-7-(3-piperidin-1-yl-propoxy)-2,3,4,5-tetrahydro-benzo[c]azepin-1-oneis prepared from2-ethyl-7-hydroxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (0.135 g, 0.66mmol) in a manner substantially analogous to Procedure K (Seeherein—Example 35) except DMF is used in place of dioxane. Followingaqueous workup, the crude material is purified by chromatography [Varian10 g SiO2 cartridge, gravity elute with 10% (25/5/1 CHCl3/MeOHNO₄OH)/90% (10% MeOH/CHCl₃)] to obtain the title compound as a colorlessoil (0.146 g, 67%). MS (ES+) 331.1.

Utilizing the procedures provided herein, in addition to methods knownin the art, compounds of Formula I were prepared. Structural figures forrepresentative examples of Formula I are shown the following pages.Example Observed Number Structure Mass 1

389 2

289 3

374 4

379 5

385 6

331 7

385 8

374 9

317 10

379 11

385 12

367 13

374 14

317 15

385 16

429 17

331 18

331 19

331 20

371 21

317 22

275 23

367 24

289 25

400 26

422 27

374 28

386 29

460 30

360 31

360 32

386 33

386 34

408 35

303 36

331

The optimal time for performing the reactions of the Schemes and theRoute can be determined by monitoring the progress of the reaction viaconventional chromatographic techniques. Furthermore, it is preferred toconduct the reactions of the invention under an inert atmosphere, suchas, for example, argon, or, particularly, nitrogen. Choice of solvent isgenerally not critical so long as the solvent employed is inert to theongoing reaction and sufficiently solubilizes the reactants to effectthe desired reaction. The compounds are preferably isolated and purifiedbefore their use in subsequent reactions. Some compounds may crystallizeout of the reaction solution during their formation and then collectedby filtration, or the reaction solvent may be removed by extraction,evaporation, or decantation. The intermediates and final products offormula I may be further purified, if desired by common techniques suchas recrystallization or chromatography over solid supports such assilica gel or alumina.

The skilled artisan will appreciate that not all substituents arecompatible with all reaction conditions. These compounds may beprotected or modified at a convenient point in the synthesis by methodswell known in the art.

The compound of Formula I is preferably formulated in a unit dosage formprior to administration. Therefore, yet another embodiment of thepresent invention is a pharmaceutical composition comprising a compoundof Formula I and one or more pharmaceutically acceptable carriers,diluents or excipients.

The present pharmaceutical compositions are prepared by known proceduresusing well-known and readily available ingredients. In making theformulations of the present invention, the active ingredient (Formula Icompound) will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a capsule,sachet, paper or other container. When the carrier serves as a diluent,it may be a solid, semisolid or liquid material that acts as a vehicle,excipient, or medium for the active ingredient. Thus, the compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (asa solid or in a liquid medium), soft and hard gelatin capsules,suppositories, sterile injectable solutions and sterile packagedpowders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

The compositions of the present invention may be formulated in sustainedrelease form to provide the rate controlled release of any one or moreof the components or active ingredients to optimize the therapeuticeffects, i.e., antihistarunic activity and the like. Suitable dosageforms for sustained release include layered tablets containing layers ofvarying disintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration, Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions may take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as a re conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active components, e.g., aneffective amount to achieve the desired purpose.

The quantity of the inventive active composition in a unit dose ofpreparation may be generally varied or adjusted from about 0.01milligrams to about 1,000 milligrams, preferably from about 0.01 toabout 950 milligrams, more preferably from about 0.01 to about 500milligrams, and typically from about 1 to about 250 milligrams,according to the particular application. The actual dosage employed maybe varied depending upon the patient's age, sex, weight and severity ofthe condition being treated. Such techniques are well known to thoseskilled in the art. Generally, the human oral dosage form containing theactive ingredients can be administered 1 or 2 times per day.

Utility

Compounds of Formula I are effective as histamine H3 receptorantagonists. More particularly, these compounds are selective histamineH3 receptor antagonists that have little or no affinity for histaminereceptor GPRv53([4R). As selective antagonists, the compounds of FormulaI are useful in the treatment of diseases, disorders, or conditionsresponsive to the inactivation of the histamine H3 receptor, includingbut not limited to obesity and other eating-related disorders. It ispostulated that selective antagonists of H3R will raise brain histaminelevels and possibly that of other monoamines resulting in inhibition offood consumption while minimizing peripheral consequences. Although anumber of H3R antagonists are known in the art, none have proven to besatisfactory obesity drugs. There is increasing evidence that histamineplays an important role in energy homeostasis. Histamine, acting as aneurotransmitter in the hypothalamus, suppressed appetite. Histamine isan almost ubiquitous amine found in many cell types and it binds to afamily of G protein-coupled receptors (GPCRs). This family provides amechanism by which histamine can elicit distinct cellular responsesbased on receptor distribution. Both the H1R and H2R are widelydistributed. H3R is primarily expressed in the brain, notably in thethalamus and caudate nucleus. High density of expression of H3R wasfound in feeding center of the brain. A novel histamine receptor GPRv53has been recently identified. GPRv53 is found in high levels inperipheral white blood cells; only low levels have been identified inthe brain by some investigators while others cannot detect it in thebrain. However, any drug discovery effort initiated around H3R mustconsider GPRv53 as well as the other subtypes.

The inventive compounds can readily be evaluated by using a competitiveinhibition Scintillation Proximity Assay (SPA) based on a H3R bindingassay using [3H] a methylhistamine as ligand. Stable cell lines,including but not limited to HEK can be transfected with cDNA coding forH3R to prepare membranes used for the binding assay. The technique isillustrated below (Preparation of Histamine Receptor Subtype Membranes)for the histamine receptor subtypes.

Membranes isolated as described in (Preparation of Histamine ReceptorSubtype Membranes) were used in a [35S]GTPχS functional assay. Bindingof [35S]GTPχS to membranes indicates agonist activity. Compounds of theinvention of Formula I were tested for their ability to inhibit bindingin the presence of agonists. Alternately, the same transfected celllines were used for a cAMP assay wherein H3R agonists inhibitedforskolin-activated synthesis of cAMP. Compounds of Formula I weretested for their ability to permit forskolin-stimulated cAMP synthesisin the presence of agonist.

Preparation of Histamine Receptor Subtype Membranes

A. Preparation H1R Membranes

cDNA for the human histamine 1 receptor (H1R) was cloned into amammalian expression vector containing the CMV promoter (pcDNA3.1(+),Invitogen) and transfected into HEK293 cells using the FuGENETranfection Reagent (Roche Diagnostics Corporation). Transfected cellswere selected using G418 (500 μ/ml). Colonies that survived selectionwere grown and tested for histamine binding to cells grown in 96-welldishes using a scintillation proximity assay (SPA) based radioligandbinding assay. Briefly, cells, representing individual selected clones,were grown as confluent monolayers in 96-well dishes (Costar ClearBottom Plates, #3632) by seeding wells with 25,000 cells and growing for48 hours (37° C., 5% CO₂). Growth media was removed and wells wererinsed two times with PBS (minus Ca²⁺ or Mg²⁺). For total binding, cellswere assayed in a SPA reaction containing 50 mM Tris-HCL (assay buffer),pH 7.6, 1 mg wheat germ agglutinin SPA beads (Amersham PharmaciaBiotech, #RPNQ0001), and 0.8 nM ³H-pyrilamine (Net-594, NEN) (totalvolume per well=200 ηl). Astemizole (10 μM, Sigma #A6424) was added toappropriate wells to determine non-specific binding. Plates were coveredwith FasCal and incubated at room temperature for 120 minutes. Followingincubation, plates were centrifuged at 1,000 rpm (˜800 g) for 10 minutesat room temperature. Plates were counted in a Wallac Trilux 1450Microbeta scintillation counter. Several clones were selected aspositive for binding, and a single clone (HIR40) was used to preparemembranes for binding studies. Cell pellets, representing ˜10 grams,were resuspended in 30 ml assay buffer, mixed by vortexing, andcentrifuged (40,000 g at 4° C.) for 10 minutes. The pellet resuspension,vortexing, and centrifugation was repeated 2 more times. The final cellpellet was resuspended in 30 ml and homogenized with a Polytron TissueHomogenizer. Protein determinations were done using the Coomassie PlusProtein Assay Reagent (Pierce). Five micrograms of protein was used perwell in the SPA receptor-binding assay.

B. Preparation H2R Membranes

cDNA for the human histamine 2 receptor was cloned, expressed andtransfected into HEK 293 cells as described above. Histamine binding tocells was assayed by SPA described above. For total binding, cells wereassayed in a SPA reaction containing 50 mM Tris-HCl (assay buffer), pH7.6, 1 mg wheat germ agglutinin SPA beads (Amersham PharmaciaBiotech,#RPNQ0001), and 6.2 nM ³H-tiotidine (Net-688, NEN) (total volume perwell=200 μl). Cimetidine (10 μM, Sigma #C4522) was added to appropriatewells to determine non-specific binding.

Several clones were selected as positive for binding, and a single clone(H2R10) was used to prepare membranes for binding studies. Fivemicrograms of protein was used per well in the SPA receptor-bindingassay.

C. Preparation of H3R Membranes

cDNA for the human histamine 3 receptor was cloned and expressed asdescribed in (Preparation of Histamine Receptor Subtye Membranes: A),above. Transfected cells were selected using G418 (500 μ/ml), grown, andtested for histamine binding by the SPA described above. For totalbinding, cells were assayed in a SPA reaction described above containing50 mM Tris-HCL (assay buffer), pH 7.6, 1 mg wheat germ agglutinin SPAbeads (Amersham Pharmacia Biotech, #RPNQ0001), and 1nM(³M)-n-alpha-methylhistamine (NEN, NET1027) (total volume perwell=200μl). Thioperimide was added to determine non-specific binding.Several clones were selected as positive for binding, and a single clone(H3R8) was used to prepare membranes for binding studies describedabove. Five micrograms of protein was used per well in the SPAreceptor-binding assay.

All compounds set forth in examples 1 to 36 exhibited affinity for theH3 receptor greater than 1 uM. Preferred compounds of the inventionexhibited affinity for the H3 receptor greater than 200 nM. Mostpreferred compounds of the invention exhibit affinity for the H3receptor greater than 20 nM.

D. Preparation of GPRv53 Membranes

cDNA for the human GPRv53 receptor was cloned and expressed as describedin (Preparation of Histamine Receptor Subtype Membranes: A), above.Transfected cells were selected, tested for histamine binding, andselected. HEK293 GPRv53 50 cells were grown to confluency in DMEM/F12(Gibco) supplemented with 5% FBS and 500 ug/ml G418 and washed withDelbecco's PBS (Gibco) and harvested by scraping. Whole cells werehomogenized with a Polytron tissuemizer in binding buffer, 50 mM Tris pH7.5. Cell lysates, 50 ug, were incubated in 96 well dishes with 3 nM(3H) Histamine and compounds in binding buffer for 2 hours at roomtemperature. Lysates were filtered through glass fiber filters (PerlinElmer) with a Tomtec cell harverster. Filters were counted with melt-onscintillator sheets (Perlin Elmer) in a Wallac Trilux 1450 MicrobetaScintillation counter for 5 minutes.

Pharmacological Results

cAMP ELISA

HEK293 H3R8 cells prepared as described above were seeded at a densityof 50,000 cells/well and grown overnight in DMEM/F12 (Gibco)supplemented with 5% FBS and 500 ug/ml G418. The next day tissue culturemedium was removed and replaced with 50 μl cell culture mediumcontaining 4 mM 3-isobutyl-1-methylxanthine (Sigma) and incubated for 20minutes at room temperature. Antagonist were added in 50 μl cell culturemedium and incubated for 20 minutes at room temperature. Agonist R(−)αmethylhistamine (RBI) at a dose response from 1×10⁻¹⁰ to 1×10⁻⁵ M wasthen added to the wells in 50 μl cell culture medium and incubated for 5minutes at room temperature. Then 50 μl of cell culture mediumcontaining 20 μM Forskolin (Sigma) was added to each well and incubatedfor 20 minutes at room temperature. Tissue culture medium was removedand cells were lysed in 0.1M HCl and cAMP was measured by ELISA (AssayDesigns, Inc.).

[35S] GTP γ [S] Binding Assay

Antagonist activity of selected compounds was tested for inhibition of[35S] GTP γ [S] binding to H3R membranes in the presence of agonists.Assays were run at room temperature in 20 mM HEPES, 100 mM NaCl, 5 mMMgCl₂ and 10 uM GDP at pH 7.4 in a final volume of 200 ul in 96-wellCostar plates. Membranes isolated from H3R8-expressing HEK293 cell line(20 ug/well) and GDP were added to each well in a volume of 50 μl assaybuffer. Antagonist was then added to the wells in a volume of 50 μlassay buffer and incubated for 15 minutes at room temperature. AgonistR(−)alpha methylhistamine (RBI) at either a dose response from 1×10⁻¹⁰to 1×10⁻⁵ M or fixed concentration of 100 nM were then added to thewells in a volume of 50 μl assay buffer and incubated for 5 minutes atroom temperature. GTP γ [35S] was added to each well in a volume of 50μl assay buffer at a final concentration of 200 pM, followed by theaddition of 50 μl of 20 mg/ml WGA coated SPA beads (Amersham). Plateswere counted in Wallac Trilux 1450 Microbeta scintillation counter for 1minute. Compounds that inhibited more than 50% of the specific bindingof radioactive ligand to the receptor were serially diluted to determinea K[i](nM). The results are given below for the indicated compound.TABLE 1 Compound Ki (nM) Structure Example 1 5.1

Example 2 0.85

To investigate the selectivity of the antagonists for the histaminereceptors, a competitive binding assay described above was performed.The ability of example 1 and 2 (structures given above) to selectivelyinhibit binding to H3R, H1R, H2R and H4R was determined. Importantly,the identification of H3R-specific antagonists that do bind the newlyidentified H4R was demonstrated. Until the present invention, most knownH3R antagonists also bound H4R. As demonstrated in Table 2, example 1and example 2 did not inhibit binding H4R in contrast to H3R. TABLE 2 Ki(nM) Compound H3R H4R H1R H2R Example 1 5.1 ≧20,000 648 813 Example 20.85 ≧20,000 1764 894

Non-imidazole containing histamine H3 receptor antagonists disclosed inthe literature generally have very poor pharmacokinetic properties (seeJ. Apelt, et al, J. Med. Chem. 2002, 45, 1128-1141). Compounds of thisinvention have markedly and unexpectedly improved pharmacokineticproperties. Male Sprague Dawley Rats (n=3 per dose arm) were separatelydosed with 3 mg/kg iv or 10 mg/kg po of compound examples 8 and 19(vehicle: water; dose volume: 1 mL/kg iv, 10 ml/kg po). Approximately0.5 mL of blood was collected in heparin collection tubes at multipletime points over an 8 or 24 hour period for examples 8 and 19respectively, and the samples were analyzed using LC/MS/MS. In thismanner compound example 8 was found to have an oral bioavailability of49% (AUC 0-8 hr; po/iv ratio) and an oral half-life of 12.2 hours.Compound example 19 was found to have an oral bioavailability of 100%(AUC 0-8 hr; poliv ratio) and an oral half-life of 12.4 hours.

From the above description, one skilled in the art can ascertain theessential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Thus, other embodiments are also within the claims.

1. A compound structurally represented by Formula I,

or pharmaceutically acceptable salts thereof, wherein: R¹ and R² areindependently H, or —OR³NR⁴R⁵, provided that one of R¹ and R² is—OR³NR⁴R⁵, and provided that only one of R¹ and R² is —OR³NR⁴R⁵; R³ is(C₂-C₅)alkylene; R⁴ is (C₁-C₄)alkyl; R⁵ is (C₁-C₄)alkyl, wherein R⁴ andR⁵ taken together with the nitrogen atom to which they are attached canform a piperidinyl or pyrrolidinyl ring; X is CH₂ or CO; Y and Z are—CH₂— or N, provided that one of Y or Z is N, and provided that only oneof Y and Z is N; R⁶ is hydrogen, —(C₁-C₄)alkyl, —CH₂-phenyl, —CH₂(C₃-C₇)cycloalkyl, —CO₂R⁸, —SO₂R⁹, —CONHR¹⁰, —COR¹¹, —CH₂CH₂NR¹²R¹³, or—CH₂R¹⁴; R⁷ is hydrogen, —(C₁-C₄)alkyl; —CH₂-phenyl,—CH₂(C₃-C₇)cycloalkyl, —CO₂R⁸, —SO₂R⁹, —CONHR¹⁰, —COR¹¹, —CH₂CH₂NR¹²R¹³,or —CH₂R¹⁴; Wherein; R⁸ is —(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl; R⁹ is—(C₁-C₄)alkyl, —(C₃-C₇)cycloalkyl, or -phenyl; R¹⁰ is —(C₁-C₄)alkyl, or—(C₃-C₇)cycloalkyl; R¹¹ is —(C₁-C₄)alkyl, —(C₃-C₇)cycloalkyl,—CH₂NR¹²R¹³, or —(C₃-C₇)cycloalkyl, wherein optionally one or more ofsaid carbons is replaced by N, NR¹⁰ or NCO₂R¹⁰; R¹² is -hydrogen, or—(C₁-C₄)alkyl; R¹³ is -hydrogen, —(C₁-C₄)alkyl, —CO₂R¹⁰, or -phenyl; R¹⁴is —(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, wherein optionally one or moreof said carbons is replaced by N, NR¹⁰, or NCO₂R¹⁰.
 2. The compound ofclaim 1, wherein R² is hydrogen and R¹ is —OR³NR⁴R⁵.
 3. The compound ofclaim 2 wherein R³ is —CH₂CH₂CH₂—.
 4. The compound of claim 3 wherein R⁴and R⁵ taken together with the nitrogen atom to which they are attachedform a piperidinyl ring.
 5. The compound of claim 1 wherein Z is N and Yis CH₂.
 6. The compound of claim 1 wherein Y is N and Z is CH₂.
 7. Thecompound of claim 1 wherein X is CO.
 8. The compound of claim 1 furtherrepresented by any one of formula (Example 1) to (Example 36) selectedfrom the group consisting of: Example Number Structure 1

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9. A pharmaceutical composition which comprises a compound of claim 1 or8 and a pharmaceutically acceptable carrier.
 10. (canceled) 11.(canceled)
 12. (canceled)
 13. A method for treatment or prevention ofobesity which comprises administering to a subject in need of suchtreatment or prevention an effective amount of a compound of claim 1 or8.
 14. The method of claim 13 wherein the antagonist is a pharmaceuticalcomposition of claim
 9. 15. A method for treatment or prevention of acognitive disorder which comprises administering to a subject in need ofsuch treatment or prevention an effective amount of a compound of claim1 or
 8. 16. The method of claim 15 wherein the antagonist is apharmaceutical composition of claim 9.